Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies
Open accessAbstract
TET2 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies including MDS, CMML, MPN, and AML. However, little is known regarding the biological function of TET2 and its role in the pathogenesis of myeloid malignancies. To study the function of TET2 in vivo, we generated a Tet2 knock out mouse model. Deletion of Tet2 in mice led to dramatic reduction in the 5-hydroxymethylcytosine levels and concomitant increase in the 5-methylcytosine levels in the genomic DNA of BM cells. The Tet2−/− mice contained an increased Lin−Sca-1+c-Kit+ (LSK) cell pool before the development of myeloid malignancies. A competitive reconstitution assay revealed that Tet2−/− LSK cells had an increased hematopoietic repopulating capacity with an altered cell differentiation skewing toward monocytic/granulocytic lineages. Approximately 1/3 of Tet2−/− and 8% of Tet2+/− mice died within 1 year of age because of the development of myeloid malignancies resembling characteristics of CMML, MPD-like myeloid leukemia, and MDS. Furthermore, transplantation of Tet2−/−, but not wild-type (WT) or Tet2+/− BM cells, led to increased WBC counts, monocytosis, and splenomegaly in WT recipient mice. These data indicate that Tet2-deficient mice recapitulate patients with myeloid malignancies, implying that Tet2 functions as a tumor suppressor to maintain hematopoietic cell homeostasis.
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“Clonal haematopoiesis does not just influence cancer development and therapeutic response but is also a major risk factor for atherosclerotic disease, which is another feature of ageing 87,88 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [88]
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- Authors
- Li, Z., Cai, X., Cai, C.-L., Wang, J., Zhang, W., Petersen, B. E., Yang, F.-C., & Xu, M.
- Affiliations
- Tisch Cancer Institute (US)
- Stem Cell Institute (PA)
- Icahn School of Medicine at Mount Sinai (US)
- Department of Pediatrics, University of Indiana, Indianapolis, IN
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-10-27
- Volume
- 118
- Issue
- 17
- Pages
- 4509-4518
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3952630
- OpenAlex
- W1976573435
- Cited by
- 671
- References
- 31
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 35 · 2023: 42 · 2022: 55 · 2021: 47 · 2020: 52 · 2019: 44 · 2018: 39 · 2017: 44 · 2016: 44 · 2015: 59 · 2014: 57 · 2013: 51 · 2012: 42
- FWCI
- 34.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL112294)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- TET2, hematopoietic stem cells, myeloid neoplasms, 5-hydroxymethylcytosine, DNA methylation, LSK cells, clonal hematopoiesis, myelodysplastic syndrome, chronic myelomonocytic leukemia, myeloproliferative neoplasms, acute myeloid leukemia, tumor suppressor, hematopoietic homeostasis
- MeSH terms
- Animals, Disease Models, Animal, DNA-Binding Proteins, Female, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Neoplasm Transplantation, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Gene Deletion, Mice, Knockout, Bone Marrow Neoplasms, Hematologic Neoplasms, Dioxygenases, Green Fluorescent Proteins, Mice
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